Cyclins were first identified in marine invertebrates on the basis of their dramatic cell cycle periodicity during meiotic and early mitotic divisions (Evans et al., Cell 33:389-396 (1983); Swenson et al., Cell 47:861-870 (1986); Standart et al., Dev. Biol. 124:248-254 (1987)). Over 30 cyclin sequences are now available for comparison. They fall into three categories; A-type, B-type, and Gl-cyclins (C, D1-D3, and E). These can be distinguished on the basis of conserved sequence motifs, patterns of appearance, and apparent functional roles during specific phases and checkpoints of the cell cycle in a variety of species (Hunt, T., Nature 350:462-463 (1991); Xiong, Y. and Beach, D., Curr. Biol. 1:362-364 (1991)).
Cyclins function by forming a complex with and activating a family of cyclin-dependent protein kinases (CDKs), at various stages in the cell cycle. The activated kinase starts a complex kinase cascade that directs the cell into DNA synthesis and/or mitosis (Draetta, G., Trends Biochem. 15:378-383 (1990); Tsai et al., Nature 353:174-177 (1991); Pagano et al., EMBO J 11:961-971 (1989)). Since the major regulatory events leading to proliferation in animal cells occur in the G1 phase of the cell cycle (Pardee, A.B., Science 246:603-608 (1989)), the deranged expression of cyclins and CDKs active in G1 may be the key to oncogenesis.
The link between oncogenesis and cyclins has been made with discovery of inappropriate expression of two cyclins in tumors (Hunter, T. and Pines, J., Cell 66:1071-1074 (1991)). First, the cyclin A gene is the site of integration of a fragment of hepatitis B virus genome in a hepatocellular carcinoma (Wang et al., Nature 343:555-557 (1990)). Cyclin A is also associated with the adenovirus transforming protein E1A in adenovirus-transformed cells (Pines, J. and Hunter T., Nature 346:760-763 (1990)). Second, in some parathyroid tumors, the Pradl (cyclin D1) locus is overexpressed due to a chromosomal rearrangement translocating it to the enhancer of the parathyroid hormone gene (Motokura et al., Nature 350:512-515 (1991)). Recently, translocation/amplification of cyclin D1 has been associated with a small percentage of other cancers including, centrocytic lymphomas, squamous cell, esophageal, and breast carcinomas (Schuuring et al., Oncogene 7:355-361 (1992); Laramie et al., Oncogene 6:439-444 (1991); Jiang et al., Cancer Res. 52:2980-2983 (1992)) .
Although these observations emphasize the importance of cyclins in cancer, the question remains of how the altered expression of only two different cyclins (i.e., cyclins A and D1), which are only very occasionally deranged, can be responsible for transformation. As yet, there have been no clear connections between cyclin derangements and cancer involving the aberrant expression of more than one cyclin, or any of the CDKs, in one type of cancer. A survey of all cyclins and CDKs in the same system of normal vs. tumor cells is essential to show whether cyclins can function collectively or redundantly in cancer by bypassing crucial checkpoints in the cell cycle.